NM_012193.4(FZD4):c.1282_1285del (p.Asp428fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000598865.9

Allele description [Variation Report for NM_012193.4(FZD4):c.1282_1285del (p.Asp428fs)]

NM_012193.4(FZD4):c.1282_1285del (p.Asp428fs)

Genes:

FZD4:frizzled class receptor 4 [Gene - OMIM - HGNC]
PRSS23:serine protease 23 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

11q14.2

Genomic location:

Preferred name:

NM_012193.4(FZD4):c.1282_1285del (p.Asp428fs)

HGVS:

NC_000011.10:g.86951472GTCT[1]
NG_011752.1:g.8914GACA[1]
NM_012193.4:c.1282_1285delMANE SELECT
NP_036325.2:p.Asp428fs
NC_000011.9:g.86662513_86662516del
NC_000011.9:g.86662514GTCT[1]
NM_012193.3:c.1282_1285del
NM_012193.3:c.1282_1285delGACA
NR_120591.3:n.835GTCT[1]
NR_120592.2:n.584GTCT[1]

Protein change:

D428fs

Links:

dbSNP: rs80358295

NCBI 1000 Genomes Browser:

rs80358295

Molecular consequence:

NM_012193.4:c.1282_1285del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_120591.3:n.835GTCT[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_120592.2:n.584GTCT[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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pyruvate decarboxylase [Nannochloropsis gaditana]
pyruvate decarboxylase [Nannochloropsis gaditana]
gi|585111045|gb|EWM28627.1||gnl|WGS |Naga_100009g44.670

Protein
Efs embryonal Fyn-associated substrate [Rattus norvegicus]
Efs embryonal Fyn-associated substrate [Rattus norvegicus]
Gene ID:290212

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000709807	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 12, 2022)	germline	clinical testing	Citation Link,
SCV002235126	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20340138, 28494495, 30452590, 28492532
SCV005198306	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000709807

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 12, 2022)

germline

clinical testing

Citation Link,

SCV002235126

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005198306

Clinical Genetics Laboratory, Skane University Hospital Lund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 8, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.

Nikopoulos K, Venselaar H, Collin RW, Riveiro-Alvarez R, Boonstra FN, Hooymans JM, Mukhopadhyay A, Shears D, van Bers M, de Wijs IJ, van Essen AJ, Sijmons RH, Tilanus MA, van Nouhuys CE, Ayuso C, Hoefsloot LH, Cremers FP.

Hum Mutat. 2010 Jun;31(6):656-66. doi: 10.1002/humu.21250.

PubMed [citation]

PMID:: 20340138

Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy.

Rao FQ, Cai XB, Cheng FF, Cheng W, Fang XL, Li N, Huang XF, Li LH, Jin ZB.

Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2623-2629. doi: 10.1167/iovs.16-21324.

PubMed [citation]

PMID:: 28494495

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000709807.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 110 amino acids are lost and replaced with one incorrect amino acid; This variant is associated with the following publications: (PMID: 20340138, 28494495, 30097784, 31827910, 31987760, 31299183, 33090715, 32238352, 33302760, 30452590)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002235126.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Asp428Serfs*2) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acid(s) of the FZD4 protein. This variant is present in population databases (rs80358295, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 20340138, 28494495, 30452590). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224625). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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